Molecular biomedicine最新文献

Evaluation of outcome indicators in trials for atopic dermatitis. 特应性皮炎试验结果指标评价。

IF 6.3

Molecular biomedicine Pub Date : 2025-05-26 DOI: 10.1186/s43556-025-00273-8

Jingru Tian, Liqing Shi, Shuntong Kang, Dingyao Zhang, Yaqing Huang, Ming Zhao, Xu Yao, Qianjin Lu

引用次数: 0

Chemoproteomics unveils Sofalcone targeting ribosomal proteins to inhibit protein synthesis in Staphylococcus aureus. 化学蛋白质组学揭示了Sofalcone靶向核糖体蛋白抑制金黄色葡萄球菌蛋白合成。

IF 6.3

Molecular biomedicine Pub Date : 2025-05-23 DOI: 10.1186/s43556-025-00269-4

Lirun Zhou, Ying Zhang, Ruishen Zhuge, Liqiong Wu, Zheng Chu, Ang Ma, Peng Gao, Yin Kwan Wong, Junzhe Zhang, Xin Peng, Peili Wang, Jigang Wang, Huan Tang

{"title":"Chemoproteomics unveils Sofalcone targeting ribosomal proteins to inhibit protein synthesis in Staphylococcus aureus.","authors":"Lirun Zhou, Ying Zhang, Ruishen Zhuge, Liqiong Wu, Zheng Chu, Ang Ma, Peng Gao, Yin Kwan Wong, Junzhe Zhang, Xin Peng, Peili Wang, Jigang Wang, Huan Tang","doi":"10.1186/s43556-025-00269-4","DOIUrl":"10.1186/s43556-025-00269-4","url":null,"abstract":"The escalating threat of antibiotic resistance, particularly in Staphylococcus aureus (including methicillin-resistant strains, MRSA), underscores the urgent need for novel therapeutics. Sofalcone (Sof), a chalcone derivative from Sophora subprostrata with established anti-inflammatory and anti-ulcer properties, exhibits promising yet underexplored antibacterial activity. Here, we demonstrate that Sof potently inhibits S. aureus and MRSA while showing minimal cytotoxicity in human cells. Notably, Sof synergized with amoxicillin, and significantly reduced the pathogenicity of S. aureus through inhibiting biofilm formation addressing key virulence factors. Through chemoproteomic profiling using a clickable Sof-derived probe, ribosomal proteins, specifically the 50S subunit protein rplB, were identified as primary targets. Sof covalently binds to rplB via cysteine residues, as validated by cellular thermal shift assays, microscale thermophoresis, and competition assays. Bio-orthogonal noncanonical amino acid tagging revealed that Sof disrupts bacterial protein synthesis by impairing ribosomal function, a mechanism distinct from conventional antibiotics. In a murine model of S. aureus-induced acute lung injury, Sof greatly reduced bacterial load in lungs, attenuated systemic inflammation, and mitigated histopathological damage. Its dual antibacterial and anti-inflammatory efficacy, coupled with activity against Gram-negative Escherichia coli, highlights broad-spectrum potential. This study unveils a covalent ribosomal-targeting strategy, positioning Sof as a multifaceted candidate against multidrug-resistant infections. Our findings bridge natural product pharmacology and mechanistic antimicrobial discovery, offering a template for combating the global antibiotic resistance crisis.","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"32"},"PeriodicalIF":6.3,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Leucine-rich repeat-containing 56 promotes breast cancer progression via modulation of the RhoA/ROCKs signaling axis. 富含亮氨酸的重复序列56通过调节RhoA/ROCKs信号轴促进乳腺癌进展。

IF 6.3

Molecular biomedicine Pub Date : 2025-05-19 DOI: 10.1186/s43556-025-00271-w

Xiqian Zhou, Jiaxin Wang, Meiling Lu, Lin Fang, Junyong Zhao, Dengfeng Li

{"title":"Leucine-rich repeat-containing 56 promotes breast cancer progression via modulation of the RhoA/ROCKs signaling axis.","authors":"Xiqian Zhou, Jiaxin Wang, Meiling Lu, Lin Fang, Junyong Zhao, Dengfeng Li","doi":"10.1186/s43556-025-00271-w","DOIUrl":"10.1186/s43556-025-00271-w","url":null,"abstract":"Breast cancer is one of the most common malignancies with a poor five-year survival rate with metastatic disease among women. It has well been documented that leucine-rich repeat-containing (LRRC) family of proteins are remarkably and aberrantly dysregulated across diverse cancer types. Notably, leucine-rich repeat-containing 56 (LRRC56) was found upregulated in metastatic breast cancer, and plays a crucial role for the movement of cilia via intraflagellar transport 88 (IFT88). However, the role for LRRC56 in breast cancer progression and regulation of IFT88 and associated pathways in metastatic progression of breast cancer has not been defined. Via in vitro functional assessments, we found that LRRC56 pivotally influences the proliferative, migratory and invasive capabilities of cancer cells. Further, via in-vivo assessments, we demonstrated that downregulation of LRRC56 effectively inhibits the growth of breast cancer xenograft tumors and their metastasis to the lungs. Mechanistically, we found that LRRC56 interacts with IFT88 to regulate yes-associated protein 1 (YAP1) expression via modulating the Ras homolog family member A (RhoA)/ Rho-associated protein kinases (ROCKs) signaling pathway. LRRC56 also regulates the expression of integrins and several other key molecules including MMP2, MMP9, FAK, as well as markers of epithelial-mesenchymal transition such as E-cadherin and N-cadherin. In summary, our results demonstrate that overexpression of LRRC56 promotes breast cancer progression via upregulating IFT88/YAP1-RhoA/ROCKs pathway, reprogramming extracellular matrix, and enhancing epithelial-mesenchymal transition. These findings highlight a critical role of LRRC56 in promoting breast cancer progression, suggesting that targeting of LRRC56 may offer a promising strategy for treating metastatic breast cancer.","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"31"},"PeriodicalIF":6.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12089637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144096077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Autoimmune bullous diseases: pathogenesis and clinical management. 自身免疫性大疱性疾病：发病机制和临床管理。

IF 6.3

Molecular biomedicine Pub Date : 2025-05-15 DOI: 10.1186/s43556-025-00272-9

Xun Feng, Huaping Zheng, Mi Wang, Yiyi Wang, Xingli Zhou, Xiwen Zhang, Jishu Li, Yue Xiao, Mintong Wei, Xiaoguang Li, Takashi Hashimoto, Jingyi Li, Wei Li

{"title":"Autoimmune bullous diseases: pathogenesis and clinical management.","authors":"Xun Feng, Huaping Zheng, Mi Wang, Yiyi Wang, Xingli Zhou, Xiwen Zhang, Jishu Li, Yue Xiao, Mintong Wei, Xiaoguang Li, Takashi Hashimoto, Jingyi Li, Wei Li","doi":"10.1186/s43556-025-00272-9","DOIUrl":"10.1186/s43556-025-00272-9","url":null,"abstract":"Autoimmune bullous diseases (AIBDs) represent a heterogeneous group of immune-mediated disorders characterized by life-threatening blistering of the skin and mucous membranes. This Review synthesizes current understanding of AIBD pathogenesis, clinical phenotypes, diagnostic approaches, and therapeutic strategies, emphasizing recent advancements and translational opportunities. At the core of AIBDs is autoantibody-mediated disruption of structural proteins in the epidermis or basement membrane zone, particularly at desmosomal and hemidesmosomal junctions. Key subtypes, including pemphigus, paraneoplastic pemphigus, pemphigoid, and IgA-related diseases, are distinguished by their target antigens, clinical manifestations, and immunopathological profiles. Diagnostic workflows rely on direct immunofluorescence, and serological assays, yet subtype differentiation remains challenging due to overlapping features. Traditional therapies, such as systemic corticosteroids and immunosuppressants, have improved outcomes but are limited by toxicity. Recent breakthroughs highlight targeted interventions, including B-cell depletion with rituximab, cytokine modulation via dupilumab, and JAK inhibitors for inflammatory pathways. Innovative strategies like chimeric autoantibody receptor T-cell (CAART) therapy further address refractory cases by eliminating autoreactive B cells. Additionally, the Review underscores the emerging role of inflammation-driven mechanisms and the necessity of multidisciplinary care, given AIBDs' associations with malignancies, autoimmune comorbidities. Despite progress, challenges persist in early diagnosis, personalized therapy optimization, and understanding antigen-specific immune responses. Future directions include refining diagnostic biomarkers, exploring novel targets, and developing precision medicine approaches.","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"30"},"PeriodicalIF":6.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel signals for naive lymphocyte recruitment under inflammation. 炎症下初始淋巴细胞募集的新信号。

IF 6.3

Molecular biomedicine Pub Date : 2025-05-13 DOI: 10.1186/s43556-025-00270-x

Weilong Zheng, Chunsheng Dong, Fangfang Zhou

引用次数: 0

MRI-based machine learning reveals proteasome subunit PSMB8-mediated malignant glioma phenotypes through activating TGFBR1/2-SMAD2/3 axis. 基于mri的机器学习揭示蛋白酶体亚基psmb8通过激活TGFBR1/2-SMAD2/3轴介导的恶性胶质瘤表型。

IF 6.3

Molecular biomedicine Pub Date : 2025-05-08 DOI: 10.1186/s43556-025-00268-5

Dongling Pei, Zeyu Ma, Yuning Qiu, Minkai Wang, Zilong Wang, Xianzhi Liu, Long Zhang, Zhenyu Zhang, Ran Li, Dongming Yan

{"title":"MRI-based machine learning reveals proteasome subunit PSMB8-mediated malignant glioma phenotypes through activating TGFBR1/2-SMAD2/3 axis.","authors":"Dongling Pei, Zeyu Ma, Yuning Qiu, Minkai Wang, Zilong Wang, Xianzhi Liu, Long Zhang, Zhenyu Zhang, Ran Li, Dongming Yan","doi":"10.1186/s43556-025-00268-5","DOIUrl":"https://doi.org/10.1186/s43556-025-00268-5","url":null,"abstract":"Gliomas are the most prevalent and aggressive neoplasms of the central nervous system, representing a major challenge for effective treatment and patient prognosis. This study identifies the proteasome subunit beta type-8 (PSMB8/LMP7) as a promising prognostic biomarker for glioma. Using a multiparametric radiomic model derived from preoperative magnetic resonance imaging (MRI), we accurately predicted PSMB8 expression levels. Notably, radiomic prediction of poor prognosis was highly consistent with elevated PSMB8 expression. Our findings demonstrate that PSMB8 depletion not only suppressed glioma cell proliferation and migration but also induced apoptosis via activation of the transforming growth factor beta (TGF-β) signaling pathway. This was supported by downregulation of key receptors (TGFBR1 and TGFBR2). Furthermore, interference with PSMB8 expression impaired phosphorylation and nuclear translocation of SMAD2/3, critical mediators of TGF-β signaling. Consequently, these molecular alterations resulted in reduced tumor progression and enhanced sensitivity to temozolomide (TMZ), a standard chemotherapeutic agent. Overall, our findings highlight PSMB8's pivotal role in glioma pathophysiology and its potential as a prognostic marker. This study also demonstrates the clinical utility of MRI radiomics for preoperative risk stratification and pre-diagnosis. Targeted inhibition of PSMB8 may represent a therapeutic strategy to overcome TMZ resistance and improve glioma patient outcomes.","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"28"},"PeriodicalIF":6.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TIM-3 teams up with PD-1 in cancer immunotherapy: mechanisms and perspectives. TIM-3与PD-1在癌症免疫治疗中的合作：机制和观点

IF 6.3

Molecular biomedicine Pub Date : 2025-05-07 DOI: 10.1186/s43556-025-00267-6

Zhuohong Yan, Chunmao Wang, Jinghong Wu, Jinghui Wang, Teng Ma

{"title":"TIM-3 teams up with PD-1 in cancer immunotherapy: mechanisms and perspectives.","authors":"Zhuohong Yan, Chunmao Wang, Jinghong Wu, Jinghui Wang, Teng Ma","doi":"10.1186/s43556-025-00267-6","DOIUrl":"https://doi.org/10.1186/s43556-025-00267-6","url":null,"abstract":"Immunotherapy using immune checkpoint inhibitors (ICIs) has become a prominent strategy for cancer treatment over the past ten years. However, the efficacy of ICIs remains limited, with certain cancers exhibiting resistance to these therapeutic approaches. Consequently, several immune checkpoint proteins are presently being thoroughly screened and assessed in both preclinical and clinical studies. Among these candidates, T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is considered a promising target. TIM-3 exhibits multiple immunosuppressive effects on various types of immune cells. Given its differential expression levels at distinct stages of T cell dysfunction in the tumor microenvironment (TME), TIM-3, along with programmed cell death protein 1 (PD-1), serves as indicators of T cell exhaustion. Moreover, it is crucial to carefully evaluate the impact of TIM-3 and PD-1 expression in cancer cells on the efficacy of immunotherapy. To increase the effectiveness of anti-TIM-3 and anti-PD-1 therapies, it is proposed to combine the inhibition of TIM-3, PD-1, and programmed death-ligand 1 (PD-L1). The efficacy of TIM-3 inhibition in conjunction with PD-1/PD-L1 inhibitors is being evaluated in a number of ongoing clinical trials for patients with various cancers. This study systematically investigates the fundamental biology of TIM-3 and PD-1, as well as the detailed mechanisms through which TIM-3 and PD-1/PD-L1 axis contribute to cancer immune evasion. Additionally, this article provides a thorough analysis of ongoing clinical trials evaluating the synergistic effects of combining PD-1/PD-L1 and TIM-3 inhibitors in anti-cancer treatment, along with an overview of the current status of TIM-3 and PD-1 antibodies.","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"27"},"PeriodicalIF":6.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of viral infectious clones and their applications based on yeast and bacterial artificial chromosome platforms. 基于酵母和细菌人工染色体平台的病毒感染性克隆及其应用。

IF 6.3

Molecular biomedicine Pub Date : 2025-04-29 DOI: 10.1186/s43556-025-00266-7

Yiyi Wu, Shangqing Gao, Guanya Liu, Mengwei Wang, Ruixiao Tan, Baoying Huang, Wenjie Tan

{"title":"Development of viral infectious clones and their applications based on yeast and bacterial artificial chromosome platforms.","authors":"Yiyi Wu, Shangqing Gao, Guanya Liu, Mengwei Wang, Ruixiao Tan, Baoying Huang, Wenjie Tan","doi":"10.1186/s43556-025-00266-7","DOIUrl":"https://doi.org/10.1186/s43556-025-00266-7","url":null,"abstract":"Infectious Clones represent a foundational technique in the field of reverse genetics, allowing for the construction and manipulation of full-length viral genomes. The main methods currently used for constructing viral infectious clones include Transformation-associated recombination (TAR), which is based on Yeast Artificial Chromosome (YAC) and Bacterial Artificial Chromosome (BAC). The YAC and BAC systems are powerful tools that enable the clones and manipulation of large DNA fragments, making them well-suited for the construction of full-length viral genomes. These methods have been successfully applied to construct infectious clones for a wide range of viruses, including coronaviruses, herpesviruses, flaviviruses and baculoviruses. The rescued recombinant viruses from these infectious clones have been widely used in various research areas, such as vaccine development, antiviral drug screening, pathogenesis and virulence studies, gene therapy and vector design. However, as different viruses possess unique biological characteristics, the challenge remains in how to rapidly obtain infectious clones for future research. In summary, this review introduced the development and applications of infectious clones, with a focus on the YAC, BAC and combined YAC-BAC technologies. We emphasize the importance of these platforms in various research areas and aim to provide deeper insights that can advance the platform and broaden its application horizons.","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"26"},"PeriodicalIF":6.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Obesity: pathophysiology and therapeutic interventions. 肥胖：病理生理学和治疗干预。

IF 6.3

Molecular biomedicine Pub Date : 2025-04-25 DOI: 10.1186/s43556-025-00264-9

Yue Kong, Haokun Yang, Rong Nie, Xuxiang Zhang, Fan Zuo, Hongtao Zhang, Xin Nian

{"title":"Obesity: pathophysiology and therapeutic interventions.","authors":"Yue Kong, Haokun Yang, Rong Nie, Xuxiang Zhang, Fan Zuo, Hongtao Zhang, Xin Nian","doi":"10.1186/s43556-025-00264-9","DOIUrl":"https://doi.org/10.1186/s43556-025-00264-9","url":null,"abstract":"Over the past few decades, obesity has transitioned from a localized health concern to a pressing global public health crisis affecting over 650 million adults globally, as documented by WHO epidemiological surveys. As a chronic metabolic disorder characterized by pathological adipose tissue expansion, chronic inflammation, and neuroendocrine dysregulation that disrupts systemic homeostasis and impairs physiological functions, obesity is rarely an isolated condition; rather, it is frequently complicated by severe comorbidities that collectively elevate mortality risks. Despite advances in nutritional science and public health initiatives, sustained weight management success rates and prevention in obesity remain limited, underscoring its recognition as a multifactorial disease influenced by genetic, environmental, and behavioral determinants. Notably, the escalating prevalence of obesity and its earlier onset in younger populations have intensified the urgency to develop novel therapeutic agents that simultaneously ensure efficacy and safety. This review aims to elucidate the pathophysiological mechanisms underlying obesity, analyze its major complications-including type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), non-alcoholic fatty liver disease (NAFLD), obesity-related respiratory disorders, obesity-related nephropathy (ORN), musculoskeletal impairments, malignancies, and psychological comorbidities-and critically evaluate current anti-obesity strategies. Particular emphasis is placed on emerging pharmacological interventions, exemplified by plant-derived natural compounds such as berberine (BBR), with a focus on their molecular mechanisms, clinical efficacy, and therapeutic advantages. By integrating mechanistic insights with clinical evidence, this review seeks to provide innovative perspectives for developing safe, accessible, and effective obesity treatments.","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"25"},"PeriodicalIF":6.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12031720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural and functional insights into metal coordination and substrate recognition of Akkermansia muciniphila sialidase Amuc_1547. 嗜muciniphila唾液酸酶Amuc_1547的结构和功能研究

IF 6.3

Molecular biomedicine Pub Date : 2025-04-23 DOI: 10.1186/s43556-025-00265-8

Tao Li, XinYue Tang, YiBo Zhu, NingLin Zhao, YingJie Song, Lihui He, XingYu Mou, Chunlei Ge, Zhenpu Chen, Hai Zhang, Xiaoxuan Yao, Xiaoyuan Hu, Jiaxing Cheng, Hong Yao, Rui Bao

{"title":"Structural and functional insights into metal coordination and substrate recognition of Akkermansia muciniphila sialidase Amuc_1547.","authors":"Tao Li, XinYue Tang, YiBo Zhu, NingLin Zhao, YingJie Song, Lihui He, XingYu Mou, Chunlei Ge, Zhenpu Chen, Hai Zhang, Xiaoxuan Yao, Xiaoyuan Hu, Jiaxing Cheng, Hong Yao, Rui Bao","doi":"10.1186/s43556-025-00265-8","DOIUrl":"https://doi.org/10.1186/s43556-025-00265-8","url":null,"abstract":"Sialidases in Akkermansia muciniphila are pivotal for mucin degradation, enabling energy acquisition, modulating gut microbiota balance, and influencing host health. However, their structural and functional mechanisms remain poorly characterized. This study resolved the magnesium-bound crystal structure of Amuc_1547, revealing a six-bladed β-propeller fold linked to a carbohydrate-binding module (CBM)-like β-sandwich domain. Structural characterization identified a conserved S-x-D-x-G-x-x-W motif, a unique metal-binding pocket coordinated by residues Glu289, Glu299, and Asp300, and a putative carbohydrate substrate-binding pocket within the CBM-like domain. Enzymatic assays confirmed the functional relevance of these structural elements and demonstrated that both metal ions and glycans significantly enhance enzymatic activity. Molecular docking, dynamics simulations, and enzyme kinetics analysis identified critical residue substitutions involved in sialic acid substrate binding and catalysis: Gln367 replaces an arginine in the classical Arg-triplet, while Gln350 and His349 replace the nucleophilic tyrosine. These substitutions collectively mediate substrate binding, nucleophilic attack, and transition state stabilization, distinguishing the catalytic mechanism of Amuc_1547 from other six-bladed β-propeller sialidases. Additionally, comparative analysis of the four A. muciniphila sialidases highlights sequence divergence and domain architecture variations, suggesting niche-specific roles in gut microenvironments. Our work not only deciphers the structural basis of metal-dependent substrate recognition in Amuc_1547 but also advances our understanding of the adaptation of A. muciniphila to gut niches, offering a blueprint for leveraging sialidase-driven mucin metabolism in microbiota-targeted therapies.","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"24"},"PeriodicalIF":6.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0